Barts-MS rose-tinted-odometer: ★ (a very Black & Red Monday)
I received an email from Laura, a young woman with very active MS, who had been on natalizumab (Tysabri) for 7 years and had recently seroconverted to being high-index JCV seropositive. She was put onto natalizumab extended interval dosing (EID), i.e an infusion every 8 weeks, to derisk PML and to reduced the number of infusions she required during the COVID-19 pandemic. Before starting her switch therapy she was told she needed to be vaccinated with the COVID-19 vaccine. Her natalizumab was stopped and whilst she was waiting for vaccine immunity to develop she developed natalizumab-rebound. This is her story.
“I’m Laura, a pwMS in the UK and I also work in the MS field. Currently, I’m not able to work due to recent rebound disease of MS, following discontinuation of Tysabri, to switch to another DMT. I believe the decision to delay the new treatment, to try to ensure I made antibodies to the second COVID-19 vaccination, was perhaps the wrong decision to be made on my behalf (I did not have any contribution to the decision, I was informed of the decision).
To risk rebound disease is not a small matter and I would urge conversations around this prior to the switch from Natalizumab (Tysabri) or Fingolimod (Gilenya) and potentially other S1P modulators (siponimod, ozanimod and ponesimod). I was in hospital for several weeks and much more disabled than I usually am; even during a typical relapse. It was a frightening and traumatic experience, and one I thought I would never endure. My mental health has also suffered as a direct result from the rebound relapse. I’m now trying to recover at home, to increase my strength and stamina sufficiently to be able to go back to driving again, working and being a Mum to two autistic boys. Independence.
I do not know of course if I will ever go back to my previous baseline. It saddens me that this was potentially avoidable; that we need to be mindful that rebound disease, by its very definition, is more severe than what has previously been experienced, and although COVID-19 vaccination is of course very important, I would have preferred to reduce my risk of rebound disease as the priority. It is my brain and spine after all. And as we know the more lesions we acquire the less reserve we have for the future. Perhaps rebound disease should be a never event, as when managed carefully it can be avoided.”
Laura’s story is tragic and should never have happened. We know enough about natalizumab rebound to prevent it from happening. It is more likely to occur in patients who have high disease activity and a high level of disability prior to starting natalizumab (see paper below). It also occurs around month 3-4 after the last infusion of natalizumab and probably slightly earlier in patients like Laura on 8-weekly EID when the steady-state levels of natalizumab are likely to lower.
There is also no scientific evidence to suggest pwMS on natalizumab will make lower antibody responses to the COVID-19 vaccine whilst on natalizumab. In our centre, this patient will have been on 6-weekly and not 8-weekly EID. She would have had all her vaccine doses whilst on natalizumab. On the day of her last natalizumab infusion, she would have had an MRI and lumbar puncture to exclude subclinical or asymptomatic PML. Provided these were negative she would have been switched to her next DMT approximately 3-4 weeks later. If for some unforeseen reason a delay was going to occur we would have given her another infusion of natalizumab. In short, we have seen too many catastrophic rebound associated relapses and would want to prevent this from happening; we know how to prevent rebound relapses so why not?
Laura, if you are reading this blog post, thank you for agreeing to allow us to publish your story and I sincerely hope you make a good recovery from your relapse. If anything can be learnt from Laura is that please don’t let vaccine-readiness delay starting a natalizumab-switch therapy.
Laura’s case illustrates my biggest fear during COVID-19 that untreated or undertreated MS is more of a concern than COVID-19. The good news is that we should be getting a definitive answer on whether or not EID is as effective as standard interval dosing (SID) in the near future from the NOVA study (ClinicalTrials.gov Identifier: NCT03689972)
Mustonen et al. Risk factors for reactivation of clinical disease activity in multiple sclerosis after natalizumab cessation. Mult Scler Relat Disord. 2020 Feb;38:101498.
Background: Natalizumab (NTZ) is widely used for highly active relapsing-remitting multiple sclerosis (MS). Inflammatory disease activity often returns after NTZ treatment discontinuation. We aimed to identify predictive factors for such reactivation in a real-life setting.
Methods: We conducted a retrospective survey in four Finnish hospitals. A computer-based search was used to identify all patients who had received NTZ for multiple sclerosis. Patients were included if they had received at least six NTZ infusions, had discontinued treatment for at least three months, and follow-up data was available for at least 12 months after discontinuation. Altogether 89 patients were analyzed with Cox regression model to identify risk factors for reactivation, defined as having a corticosteroid-treated relapse.
Results: At 6 and 12 months after discontinuation of NTZ, a relapse was documented in 27.0% and 35.6% of patients, whereas corticosteroid-treated relapses were documented in 20.2% and 30.3% of patients, respectively. A higher number of relapses during the year prior to the introduction of NTZ was associated with a significantly higher risk for reactivation at 6 months (Hazard Ratio [HR] 1.65, p < 0.001) and at 12 months (HR 1.53, p < 0.001). Expanded Disability Status Scale (EDSS) of 5.5 or higher before NTZ initiation was associated with a higher reactivation risk at 6 months (HR 3.70, p = 0.020). Subsequent disease-modifying drugs (DMDs) failed to prevent reactivation of MS in this cohort. However, when subsequent DMDs were used, a washout time longer than 3 months was associated with a higher reactivation risk at 6 months regardless of whether patients were switched to first-line (HR 7.69, p = 0.019) or second-line therapies (HR 3.94, p = 0.035). Gender, age, time since diagnosis, and the number of NTZ infusions were not associated with an increased risk for reactivation.
Conclusion: High disease activity and a high level of disability prior to NTZ treatment seem to predict disease reactivation after treatment cessation. When switching to subsequent DMDs, the washout time should not exceed 3 months. However, subsequent DMDs failed to prevent the reactivation of MS in this cohort.
Riancho et al. Does Extended Interval Dosing Natalizumab Preserve Effectiveness in Multiple Sclerosis? A 7 Year-Retrospective Observational Study. Front Immunol. 2021 Mar 25;12:614715.
The extended interval dosing (EID) of natalizumab has been suggested to be associated with a reduced risk of progressive multifocal leukoencephalopathy (PML) and short-term preservation of efficacy but its long-term effectiveness remain unknown. We aimed to determine the long-term effectiveness and safety of natalizumab in an EID setting in a cohort of patients with multiple sclerosis (MS) treated for more than 7 years. We conducted an observational retrospective cohort study, including 39 (34 female, 5 male) patients with clinically definite relapsing-MS, initially treated with standard interval dosing (SID) of natalizumab (mean time 54 months [SD29]) who were then switched to EID, every 8 weeks (mean time 76 months [SD13]). The main outcome measures included the following: i) annualized relapse rate (ARR), ii) radiological activity, iii) disability progression, and iv) NEDA-3 no evidence of disease activity index. EID preserved ARR, radiological activity, and prevented disability worsening during follow-up. The proportion of patients maintaining their NEDA-3 status after 24, 48, and 72 months of natalizumab administration in EID was 94%, 73%, and 70%, respectively. Stratified analysis according to history of drug therapy showed that the EID of natalizumab was slightly more effective in naïve patients than in those previously treated with other immunosuppressive drugs. No cases of PML or other severe adverse reactions were reported. In conclusion, long-term therapy with natalizumab in an EID setting following an SID regimen maintained its disease-modifying activity, and was safe and well tolerated for over 7 years. These encouraging observational results need to be confirmed in controlled clinical trials.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.
